ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response

Nature ◽  
2000 ◽  
Vol 405 (6785) ◽  
pp. 477-482 ◽  
Author(s):  
Xiaohua Wu ◽  
Velvizhi Ranganathan ◽  
David S. Weisman ◽  
Walter F. Heine ◽  
David N. Ciccone ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nijmegen Breakage Syndrome ◽  
Damage Response ◽  
Syndrome Protein

scholarly journals Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis

2007 ◽  
Vol 204 (5) ◽  
pp. 1003-1011 ◽  
Author(s):  
Simone Difilippantonio ◽  
Arkady Celeste ◽  
Michael J. Kruhlak ◽  
Youngsoo Lee ◽  
Michael J. Difilippantonio ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nijmegen Breakage Syndrome ◽  
Radiation Sensitivity ◽  
Terminal Region ◽  
Cell Cycle Checkpoint ◽  
Artificial Chromosomes ◽  
Downstream Target ◽  
Gonadal Dysfunction ◽  
Damage Response

The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We find that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response.

scholarly journals Impaired p53-mediated DNA damage response contributes to microcephaly in Nijmegen Breakage Syndrome patient-derived cerebral organoids

2020 ◽  
Author(s):  
Soraia Martins ◽  
Lars Erichsen ◽  
Angeliki Datsi ◽  
Wasco Wruck ◽  
Wolfgang Goering ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Induced Pluripotent Stem Cell ◽  
Nijmegen Breakage Syndrome ◽  
Damage Repair ◽  
Damage Response ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within NBN, a DNA-damage repair protein. Hallmarks of NBS include several clinical manifestations such growth retardation, chromosomal instability, immunodeficiency and progressive microcephaly. However, the etiology of microcephaly in NBS patients remains elusive. Here, we employed induced pluripotent stem cell-derived brain organoids from two NBS patients to analyze the underlying mechanisms of microcephaly. We show that NBS-organoids carrying the homozygous 647del5 NBN mutation are significantly smaller in size with disrupted cyto-architecture Patient-derived organoids exhibit premature differentiation together with neuronatin (NNAT) overexpression and key pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. Moreover, we show that after exposure to bleomycin, NBS organoids undergo a delayed p53-mediated DNA damage response and aberrant trans-synaptic signalling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.

scholarly journals The hMre11/hRad50 Protein Complex and Nijmegen Breakage Syndrome: Linkage of Double-Strand Break Repair to the Cellular DNA Damage Response

Cell ◽  
1998 ◽  
Vol 93 (3) ◽  
pp. 477-486 ◽  
Author(s):  
James P Carney ◽  
Richard S Maser ◽  
Heidi Olivares ◽  
Elizabeth M Davis ◽  
Michelle Le Beau ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Complex ◽  
Nijmegen Breakage Syndrome ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Damage Response ◽  
Break Repair ◽  
Cellular Dna

2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2118-P
Author(s):  
CHAY TENG YEO ◽  
BRYNDON OLESON ◽  
JOHN A. CORBETT ◽  
JAMIE K. SCHNUCK
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Damage Response
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